Clinical trials provide the highest standard of evidence for HIV/TB co-infected patients, but they utilize substantial resources in terms of personnel, subjects, time, and cost. Ongoing research questions regarding both diagnosis and management of co-infected patients lead to many clinical trial concepts, not all of which can viably be pursued. This renewal application to NIAID will uniquely apply a mathematical simulation modeling framework, based on the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Model, to the NIAID clinical trials infrastructure. In the first 3 years of the initial award, we have used these novel methods to publish 17 papers (and 2 editorials) related to the conduct, design, and value of HIV/TB-related clinical trials, including one in The New England Journal of Medicine. We now propose 2 new specific aims: 1) To develop and advance the practical use of methods for Value of Information (VOI) analysis, particularly to estimate the Expected Value of Sample Information (EVSI) of potential clinical trials. EVSI offers insight into whether further trial-based research is beneficial; into the extent of that benefit gien current pre-trial information; and into the most efficient trial size and design. We will streamlin computational approaches and assess the marginal benefits and costs of changes associated with alternative trial sample sizes. 2) To inform clinical trial design and priority setting in th area of HIV/TB by conducting a series of policy evaluations that leverage the analytic advances developed in the prior cycle and in Aim 1. Long-acting pre-exposure prophylaxis (LA-PrEP). We will examine the value of mounting an LA- PrEP trial in resource-limited settings, taking into account both the projected incremental efficacy benefit, as well as the drug and management costs of LA-PrEP. *Tuberculosis diagnostics. We will assess the value of a clinical trial of novel TB diagnostics at the time of HIV diagnosis in TB endemic areas. We will account for uncertainty in empiric TB therapy rates and examine the incremental benefit of larger trial sample sizes given increased trial costs. HIV cure. We will examine critical benchmarks for the viability of a trial of alternative HIV cure strategies in resource-limited settings. These benchmarks include: population eligibility, intervention efficacy and toxicity, relapse and re-infection rates, quality of life benefits, and costs. The ultimate goal of this proposal is to help decision makers choose the best possible use of scarce clinical trial resources by developing and disseminating novel methods to understand the value of information of proposed HIV/TB-related trials over the next decade.